Role of breast cancer resistance protein in the bioavailability and fetal penetration of topotecan
Role of breast cancer resistance protein in the bioavailability and fetal penetration of topotecan
复制标题
DOI：
10.1093/jnci/92.20.1651
复制
发表时间：
2000-10-18
影响因子：
10.3
通讯作者：
Schinkel, AH
中科院分区：
文献类型：
--
作者：
Jonker, JW;Smit, JW;Schinkel, AH
背景和方法：乳腺癌耐药蛋白（BCRP/MXR/ABCP）是一种多药耐药蛋白，是药物转运蛋白三磷酸腺苷结合盒家族的成员。BCRP可以使肿瘤细胞对抗癌药物拓扑替康、米托蒽醌、阿霉素和柔红霉素产生耐药性。为了研究BCRP的生理作用，我们使用极化的哺乳动物细胞系来确定BCRP药物转运的方向。我们还使用BCRP抑制剂GF 120918来评估BCRP在保护小鼠免受异生物质药物的作用。BCRP的鼠同源物Bcrp 1在极化哺乳动物细胞系LLC-PK 1和MDCK-II中表达，并确定了Bcrp 1介导的拓扑替康和米托蒽醌转运方向。为了避免P-糖蛋白（P-gp）提供的混淆药物转运，在野生型和P-gp缺陷小鼠及其胎儿中研究了Bcrp 1在拓扑替康生物利用度中的作用和GF 120918的作用。结果如下：Bcrp 1介导极化细胞系中药物的顶端定向转运，当拓扑替康和GF 120918口服给药时，在P-gp缺陷小鼠中，血浆中的托泊替康浓度（即，给药后药物可用于靶组织的程度）显著增加（大于六倍）和野生型小鼠（大于九倍），与对照（即，载体处理的）小鼠。此外，用GF 120918处理降低了托泊替康的血浆清除率和肝胆排泄，并增加了小肠的（再）摄取。在妊娠GF 120918给药的P-gp缺陷小鼠中，托泊替康的相对胎仔渗透率是妊娠溶媒给药小鼠的2倍，表明BCRP在胎盘的母胎屏障中发挥作用。结论：Bcrp 1介导药物的顶端定向转运，降低药物的生物利用度，并保护胎儿免受药物的侵害。因此，我们认为BCRP抑制剂的策略性应用可能导致拓扑替康或其他BCRP底物药物更有效的口服化疗。
Background and Methods: Breast cancer resistance protein (BCRP/MXR/ABCP) is a multidrug-resistance protein that is a member of the adenosine triphosphate-binding cassette family of drug transporters. BCRP can render tumor cells resistant to the anticancer drugs topotecan, mitoxantrone, doxorubicin, and daunorubicin, To investigate the physiologic role of BCRP, we used polarized mammalian cell lines to determine the direction of BCRP drug transport. We also used the BCRP inhibitor GF120918 to assess the role of BCRP in protecting mice against xenobiotic drugs. Bcrp1, the murine homologue of BCRP, was expressed in the polarized mammalian cell lines LLC-PK1 and MDCK-II, and the direction of Bcrp1-mediated transport of topotecan and mitoxantrone was determined. To avoid the confounding drug transport provided by P-glycoprotein (P-gp), the roles of Bcrp1 in the bioavailability of topotecan and the effect of GF120918 were studied in both wild-type and P-gp-deficient mice and their fetuses. Results: Bcrp1 mediated apically directed transport of drugs in polarized cell lines, When both topotecan and GF120918 were administered orally, the bioavailability (i,e,, the extent to which a drug becomes available to a target tissue after administration) of topotecan in plasma was dramatically increased in P-gp-deficient mice (greater than sixfold) and wild-type mice (greater than ninefold), compared with the control (i,e., vehicle-treated) mice. Furthermore, treatment with GF120918 decreased plasma clearance and hepatobiliary excretion of topotecan and increased (re-)uptake by the small intestine. In pregnant GF120918-treated, P-gp-deficient mice, relative fetal penetration of topotecan was twofold higher than that in pregnant vehicle-treated mice, suggesting a function for BCRP in the maternal-fetal barrier of the placenta. Conclusions: Bcrp1 mediates apically directed drug transport, appears to reduce drug bioavailability, and protects fetuses against drugs. We propose that strategic application of BCRP inhibitors may thus lead to more effective oral chemotherapy with topotecan or other BCRP substrate drugs.